Paclitaxel, originally isolated from the bark of Pacific Yew tree, has been established as one of the most effective chemotherapeutic drugs for a range of cancer types including lung, ovarian, and breast cancers. A major limitation of paclitaxel is its low solubility and the need to be formulated in toxic organic solvents, typically polyoxyethylated castor oil and dehydrated ethanol mixtures (known as TAXOL®). To prevent the solvent toxicity paclitaxel has been formulated with a variety of excipients as well as using nanoparticle delivery systems that can improve the solubility of hydrophobic drugs such as paclitaxel.
ABRAXANE®, a paclitaxel albumin bound nanoparticle formulation was approved by FDA in 2005 and is currently one of the best formulations of paclitaxel for chemotherapy. Other systems have been investigated for the delivery of paclitaxel or are in development, e.g., using polymeric nanoparticles, lipid-based nanoparticle formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, or cyclodextrin nanoparticles (see, for example, Ping Ma et al., 2013, J Nanomed. Nanotechnology:4:2).
Although ABRAXANE® is a widely used chemotherapeutic agent and practically applicable to all cancer types, the response to ABRAXANE®, however, can be as low as 20%. The relative insensitivity to paclitaxel found in some patients could be a contributing factor to low response rate. However, this insensitivity may not the primary reason for the low response rate. There is up to 10-fold variations in blood concentration of paclitaxel monitored in clinical patients' samples when dosed at the various approved doses (260 mg/m2 for metastatic breast cancer, 125 mg/m2 for pancreatic cancer, and 100 mg/m2 for lung cancer (Nyman DW et al., 2005, J Clin. Oncol. 23, 7785-93). This variation suggests that the vast majority of patients are potentially dosed incorrectly with either too great a concentration of paclitaxel administration, and had to be taken off the treatment, or too low a dosage administered and providing no benefit from the treatment. Even if patients are sensitive to paclitaxel, having an insufficient drug level would render them nonresponsive and the treatment ineffective. The under-dosed group is the most vulnerable patient population, as it is difficult to determine whether they are insensitive to paclitaxel or not administered sufficient paclitaxel. Full pharmacokinetic (PK) profiling is the only approach in such cases to provide guidance for proper drug dose based on the individual pharmacokinetic variation.
Currently there are no available methods to perform a full PK quantitation of paclitaxel without having the patient enrolled in comprehensive clinical testing, which requires a hospital stay. Typical duration of such PK testing may be over a 48 hour period and includes repetitive blood drawing. Presently, the use of complex laboratory equipment is required to analyze blood concentration of paclitaxel, including liquid chromatography/mass spectrometry (LC/MS) methods. These methods are extremely costly, currently over $120/sample and the equipment cost is in the range exceeding $150K-$200K per instrument. It has also been demonstrated that a minimum of four data points collected over a period of 48 to 72 hours is needed to adequately characterize the PK parameters for each particular patient. Keeping the patients in hospital for PK testing can easily push the cost to roughly $10,000 per patient. A sufficiently powered Phase III clinical trial to demonstrate clinical efficacy for PK guided dosing would require 500 patients (250 patients for BSA dosing and 250 patients for PK guided dosing). The bioanalytical cost alone would be $1.5M (500 points×6 cycles of chemotherapy×4 blood samplings for PK analysis×$120/sample analysis). The other components of trial would cost roughly $100,000 per patient, totaling $50M. This represents a significant barrier to obtaining meaningful clinical data necessary to guide dose adjustment for optimum tumor response and regulatory approval of the device. The high cost of the analysis and instrumentation, therefore, has prohibitive consequences on establishing therapeutic drug monitoring (TDM) for many drugs that have a relatively narrow therapeutic range.
Accordingly, a need remains for a simple, effective, and inexpensive approach to monitor the pharmacokinetics of paclitaxel in a patient, thereby appropriately personalizing the therapy to the individual patient by informing any adjustment of the dosing strategy. The present invention seeks to fulfill this need and provides further related advantages.